Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Despite numerous efforts to target epidermal growth factor receptor (EGFR), commonly dysregulated in GBM, approaches directed against EGFR have not achieved the same degree of success as seen in other tumor types, particularly as compared to non-small cell lung cancer (NSCLC). EGFR alterations in glioblastoma lie primarily in the extracellular domain, unlike the kinase domain alterations seen in NSCLC. Small molecule inhibitors are difficult to develop for the extracellular domain. Monoclonal antibodies can be developed to target the extracellular domain but must contend with the blood brain barrier (BBB). We review the role of EGFR in GBM, the history of trialed treatments, and the potential paths forward to target the pathway that may have greater success.
Highlights
Glioblastoma (GBM) is an aggressive primary brain tumor
Challenges to targeting of epidermal growth factor receptor (EGFR) include heterogeneity of EGFR mutant and wild-type expression [58,59,111], adverse effects arising from collateral inhibition on wild-type EGFR in normal tissues, reduced penetration of monoclonal antibodies across the blood brain barrier, and escape mechanisms such as the PI3K and MET pathways
The prevalence of EGFR mutation is far higher in glioblastoma than it is for non-small cell lung cancer (NSCLC)—suggesting its greater importance in glioblastoma biology
Summary
Glioblastoma (GBM) is an aggressive primary brain tumor. There are over 10,000 new diagnoses of GBM in the United States each year. Approach to treatment of GBM has changed little in the intervening years, despite hundreds of interventional trials since this paradigm was first published in. Concerted efforts at targeting specific genetic alterations in glioblastoma have largely failed. Chief among these targets is epidermal growth factor receptor (EGFR), the most commonly altered receptor tyrosine kinase and one of the most common alterations in glioblastoma [7]. Attempts to target EGFR in glioblastoma have had minimal success, especially in comparison to other tumors such as non-small cell lung cancer (NSCLC). The failure of EGFR-directed treatments and other targeted therapies has been ascribed to the high intra-tumoral heterogeneity of glioblastoma, but other obstacles likely play a role as well. This review focuses on both the history and future of targeting EGFR in glioblastoma, with a special emphasis on tyrosine kinase inhibitors that have already achieved success in EGFR mutant NSCLC
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